Millions of Americans suffer from chronic neuropathic pain, which is often refractory to current treatment. In search of a solution to this problem of chronic, untreatable pain, we intend to develop a new analgesic therapy based on modulation of the T-type Ca2+ channel. T-type Ca2+ channels play key roles in pain signaling. The Cav3 family of channels is involved in at least two key stages of pain pathways: first, at the dorsal root ganglion (DRG) and again at the thalamic pain relay. Both chronic nerve constriction injury and diabetic neuropathy cause upregulation of one of these channels (Cav3.2) in the DRG neurons of rats. Conversely, gene knockout, antisense knockdown, or silencing of the Cav3.2 isoform produces good apparent pain relief in both neuropathic and inflammatory pain in rats or mice. In short, the T-type Ca2 channels appear to be excellent drug targets for treating neuropathic pain. In our completed T-channel biologic probe discovery project (NS050771/Xie), through collaboration with the Vanderbilt Screening/Chemistry Center, we discovered four hit compounds from two different novel chemical scaffolds. The best hit, ML218, mitigates chronic pain induced by spared nerve injury, streptozotocin-induced diabetic neuropathy and reserpine-induced chronic pain in rats. We have therefore selected ML218 as the starting compound for chemical optimization in our proposed SBIR Fast-Track project for our pain-relief drug discovery program. We will start with structure-activity relationship (SAR) studies on a focus set of ML218 derivatives. The milestone for advancement from Phase I to Phase II is identification of the top 10 modified leads that meet our selection criteria (higher potency and selectivity than ML218). The milestone for the end of Phase II is the production of a therapeutic candidate, generation of sufficient data of in vivo efficacy, pilot safety pharmacology, and nonGLP toxicology which will help us to make a go/no-go informed decision for IND- enabling studies in a Competing Renewal of SBIR Phase II. Once we are ready to conduct IND-enabling studies and file an IND application, it will be enormously valuable in attracting non-government support and industrial partners for clinical development. Our ultimate goal is to develop a novel therapeutic with selective and state-dependent inhibition of the Cav3 channel to treat chronic neuropathic pain.